Project Summary Myocardial infarction (MI) occurs in ~900,000 Americans annually accounting for a mortality of 7-18%. While percutaneous coronary intervention (PCI) is invariably successful in restoring epicardial patency, significant microvascular obstruction (MVO) resulting in the ?no-reflow phenomenon? (NRF) occurs frequently which significantly impacts mortality and the development of CHF. Current devices are only partially effective in mitigating MVO and NRF following PCI for MI. Adenosine attenuates many of the mechanisms responsible for MVO and NRF. Seminal studies in our laboratory demonstrated that intravenous adenosine resulted in striking vascular and myocardial protection and this was subsequently confirmed in large clinical trials. Adenosine?s full potential is compromised due to its ultra-short half-life. Since the guidewire is the first PCI device deployed into the coronary vascular bed, we developed a simple, two-step procedure to make a pentameric form of adenosine (PA) that can be coated onto guidewires (Adenowire) and allows for continuous and sustained elution of adenosine into the coronary circulation during PCI. We validated the structure of PA with NMR, its stability by calorimetry and confirmed its safety with biocompatibility tests. We also demonstrated that PA released adenosine in vitro over 60 mins. Porcine studies demonstrated that pharmacologically active amounts of adenosine are released as verified by a significant and sustained increase in coronary blood flow following wire insertion. Since our initial submission of this grant proposal we have developed strong relationships with industry leading guidewire and coating companies resulting in the production of a viable commercial product. The goal of this Phase II application is to advance this novel technology to the clinical arena. We will utilize a LDLR knockout swine model which manifests hypercholesterolemia and human-like atherosclerotic lesions. Two important mechanisms of MVO will be tested: 1) efficacy of Adenowire to reverse potent smooth muscle vasoconstrictors; and 2) effect of Adenowire to ameliorate cellular obstruction by endothelial cells and formed elements thereby attenuating NRF following regional ischemia and reperfusion. The data obtained from these studies will be invaluable in advancing this highly novel guidewire device to clinical trials. The concept is transformative and has a high likelihood of success since it will deliver high concentrations of adenosine directly at the target site throughout the PCI procedure. If clinical trials confirm that Adenowire is effective in preventing MVO and NRF it would represent a major advance in treatment of MI patients. This would have important societal and economic benefits for MI patients treated with PCI in the US each year.